The furanosteroids are a class of novel pentacyclic fungal metabolites that share in common a furan ring bridging positions 4 and 6 of the steroid skeleton (MacMillan, et al. (1968) Chem. Commun. pg. 613; MacMillan, et al. (1972) J. Chem. Soc., Chem. Commun. pg. 1063; MacMillan, et al. (1972) J. Chem. Soc. Perkin I pg. 2892; MacMillan, et al. (1972) J. Chem. Soc. Perkin I pg. 2898; Simpson, et al. (1978) J. Chem. Soc. Perkin I pg. 979; Haefliger, et al. (1973) Helv. Chim. Acta 56:2901; Brian & McGowan (1945) Nature (London) 156:144; Aldridge, et al. (1975) J. Chem. Soc. Perkin I pg. 943; Hanson, et al. (1985) J. Chem. Soc. Perkin Trans I pg. 1311; Hanson (1995) Nat. Prod. Rep. pg. 381; Wipf & Kerekes (2003) J. Nat. Prod 66:716-718).

Members of this class are known for their powerful anti-inflammatory and antibiotic properties (Brian & McGowan (1945) supra). These compounds have also been shown to selectively block certain intracellular signaling pathways, in particular those associated with cell growth and development (Powis, et al. (1994) Cancer Res. 54:2419; Ward, et al. (2003) Chem. Biol. 10:207; Liu, et al. (2005) Chem. Biol. 12:99-107). As such, furanosteroids are useful as therapeutic agents for diseases characterized by rapid cell proliferation, including cancer (Ward, et al. (2003) supra). Representative examples include members of the viridin and wortmannin families, distinguished by an aromatic ring C in the former and a strained lactone ring A in the latter. The growth inhibitory properties of these compounds stem partly from their activity as irreversible inhibitors of phosphoinositide 3-kinase (PI3K), a class of enzymes that play a key role in important cell signaling processes (Powis, et al. (1994) supra). In addition, wortmannin has been shown to inhibit mammalian Polo-like kinase, a vital enzyme in cellular growth cycles.
Structure-activity studies have identified C20 of the furanosteroid skeleton in both families as a crucial site for PI3-kinase inhibition, most likely due to the highly electrophilic nature of the furan ring (Norman, et al. (1996) J. Med. Chem. 39:1106; Wymann, et al. (1996) Mol. Cell. Biol. 16:1722; Dodge, et al. (1995) Biorg. Med. Chem. Lett. 5:1713; Haefliger, et al. (1975) Helv. Chim. Acta 58:1620; Haefliger & Hauser (1975) Helv. Chim. Acta 58:1629; Walker, et al. (2000) Mol. Cell. 6:909; Wipf, et al. (2004) Org. Biomol. Chem. 2:1911-1920). It is believed that irreversible inhibition occurs by nucleophilic addition of the kinase to C20, a process that is facilitated by the C3 and C7-carbonyl groups. In vitro studies support this, since both amines and thiols rapidly open the furan ring (Wymann, et al. (1996) supra). This reactivity has been exploited to prepare a library of ring-opened analogs of wortmannin, some of which have superior activity/selectivity profiles compared to the parent compound (Wipf, et al. (2004) supra). Also, modifications in ring D have shown this region to be an important enzyme recognition site. For example, 17β-OH wortmannin, with an IC50 of 0.5 nM, was the first known subnanomolar inhibitor of PI3-kinase, indicating that even more potent members of this class might be developed (Dodge, et al. (1995) supra).
However, analysis of wortmannin and viridin derivatives has been hindered by the many difficulties associated with synthesizing these compounds (Broka & Ruhland (1992) J. Org. Chem. 57:4888; Sato, et al. (1996) Tetrahedron Lett. 37:6141; Honzawa, et al. (1999) Tetrahedron Lett. 40:311; Mizutani, et al. (2002) Angew. Chem. Int. Ed. 41:4680; Wipf & Kerekes (2003) 225th ACS National Meeting, New Orleans, La.; Wipf & Halter (2005) Org. Biomol. Chem. 3:2053-2061; Moffatt (1966) J. Chem. Soc. (C) pg. 734; Yasuchika, et al. (1987) Chem. Commun. pg. 515; Carlina, et al. (1997) J. Org. Chem. 62:2330; Souza & Rodrigo (1999) Chem. Commun. pg. 1947; Boynton, et al. (1999) J. Chem. Research (S) pg. 638; Wright, et al. (2001) 221st ACS National Meeting; Wright, et al. (2002) Tetrahedron Lett. 43:943; Anderson, et al. (2004) Angew. Chem. Int. Ed. 43:1998). Only one total synthesis of viridin has been reported (Anderson, et al. (2004) supra), and two syntheses of wortmannin (Sato, et al. (1996) Tetrahedron Lett. 37:6141; Mizutani, et al. (2002) Angew. Chem. Int. Ed. 41:4680). The furanosteroid skeleton itself has also proven to be a significant synthetic challenge. Therefore, to synthesize structural analogs of known furanosteroids, there is a need in the art for a concise synthetic approach for preparing the furanosteroid skeleton. The present invention meets this need in the art.